17-oxygenated 5alpha-androstan-19-ols and esters thereof



Patented May 38, .5365

United States Patent cc WW 3 184 487 The compounds of the present invention are convena iently produced from starting materials represented by "'OXYGENATED 5"ANDR0STAN190Ls the following structural formulas AND ESTERS THEREGF Raymond E. Counsell, Skokie, and Paul D. Klimstra, CH3 Northbrook, 111., assignors to G. D. Searle 8: 30., Chi- 5 0 cago, 111., a corporation of Delaware I No Drawing. Filed Sept. 16, 1963, Ser. No. 309,287

13 tllaims. (Cl. 26tl--397.4)

The invention disclosed herein is concerned with androstane derivatives characterized by an unsubstituted HO saturated A-ring and, in particular, with l7-oxygenated 5a-androstan-l9-ols and the lower alkanoyl esters thereof, 7 5 said compounds encompassed by the following structural H representations 15 v oz 3 CH3 4 H OH! I 0o 2 (lower alkyl) and CH wherein X 1s a halogen of atomic weight less than 100, g i.e., fluorine, chlorine, or bromine, and Z can be hydro- (3H2 0 gen or a lower aliphatic hydrocarbon radical. Those 3 starting materials together with methods for their manufacture are disclosed in US. Patent 3,018,298, issued January 23, 1962. As described in our copending application Serial No. 293,839, filed July 9, 1963, oxidation of those halohydrins with a suitable reagent results in the corresponding 2,8,19-epoxy compounds. Thus, a suitable process involves the reaction of 3a-bIOI110-2fi- H hydroxy-iwandrostaml7-one in carbon tetrachloride with in which X is Symbolic of hydrogen or a lower aliphatic lead testraacgtatet 57 i to 35031 EJ hydrocarbon radical, and Y and Z can be either hydrogen 4O 2 3 b or a radical represented by the formula e atter B, -epoxy mterme lates can e converte to the corresponding 19-acetoxyandrost-2-enes by a proc-' ess which involves the use of a reagent consisting of zinc l alkyl) and acetic acld. The process in question is typically conducted at the reflux temperature of the reaction mix- The term lower aliphatic hydrocarbon radical desigture over a period of several hours. A specific example nated by X in the foregoing representation encompasses of the process involved is the reaction of 3OL-bI'OITiO-2fi,l9- those groups more particularly defined by the following epoXy-5a-androstan-l7-one with zinc and acetic acid, at fo ula the reflux temperature, to produce 19-acet'o y-5a-androst- C H 2-en-17-one. The latter intermediate, upon'catalytic hyc H drogenation 1n the presence of 5% 'palladlum-on-carbon n catalyst, affords the instant l9-acet-oxy-5wandrostan-l7- and C H one. Reduction of the 17-keto group of that substance with lithium aluminum'hydride in tetrahydrofuran results in Sa-RDdI'OStEtIlB-l713,19-(ll0l, while substitution of the reagent lithium tri-(tertiarybutoxy) aluminum hydride in in which n is indicative of a positive integer from 1 to 7 inclusive. Examples of the groups envisaged are ethynyl,

propenyl, allyl, crotyl, butynyl, methyl, isobutyl, second that process leaves the ester group intact, thus affording ary-propyl, pentenyl, hexynyl, heptyl, propargyl, neo- 5wa11dr08lane-17fiJ9-diOI -a iat pentyl, heptynyl, vinyl, and heptenyl. The lower alkyl The Una-(lower alkyl)- l7,6-hydroxy compounds of this radicals encompassed by the Y and Z terms are those invention are conveniently obtained by reaction of the represented by the formula instant I7-ones with the appropriate alkyl organometallic C H reagent. An example of that process is the reaction of n 2M1 19-acetoxy-5m-androstan-17-one with methyl magnesium defined above, and are exemplified by methyl, ethyl, bromide in ether solution, thus resulting in 17ot-methyl secondary-butyl, hexyl, and tertiary-heptyl. Sa-androstane-175,19-di0l.

Those derivatives possessing an unsaturated hydrocarbon grouping at the 17-position can be produced in an analogous manner by reacting the instant 17-keto substances'with the desired organometallic reagent. When the aforementioned 19-acetoxy 50c -.andros tan-17-one is contacted with the 30% lithium acetylide-70% ethylene diamine complex, for example, 17a ethynyl 50c androstane-17fi,19-diol is produced. An alternate method particularly suited to the manufacture of the 17ix-(lower alkenyl) derivatvies involves partial reduction of the cor responding 17a-(lower alkynyl) compounds. The instant 17u-vinyl-5a-androstane-17B,19-diol, typically, is obtained by hydrogenation of 17or-ethynyl-5a-androstanel7fl,19- di-ol in the presence of a 5% palladium-on-carbon catalyst.

The instant 19-hydroxy derivatives are obtained upon hydrolysis of the aforementioned l9-acetoxy compounds and can be converted to the 19-(lower alkanoyl)oxy compounds of this invention by esterification with a suitable .acylating agent such as a lower alkanoic acid anhydride or halide. That acylation reaction is preferably conducted in the presence of an acid acceptor such as triethylamine or pyridine. An example of those processes is the saponification of l9-acetoxy5a-androstan-17-one with potassium hydroxide in aqueous methanol to afford 19-hydroxy-5aandrostan-17-one and the acylation of the latter 19-01 with propionic .anhydride and pyridine, resulting in 19-p'r0- pionoxy-5a-androstan-17-one. In a similar manner, 5aandrostane-l75,19-di=ol 19-acetate isacylated with acetic anhydride and pyridine to afford 5a-androstane-l7fi,19- diol 17,19-diacetate.

. 4L V in a 1:1 hexane-benzene solution, then is chromatographed on a silica gel column. The column is eluted, first with benzene then with benzene containing increasing amounts of ethyl acetate. The 5% ethyl acetate in benzene eluate aifords a fraction which, after recrystallization from methanol, results in 3a-brorno-2p,19-epoxy-5a-androstan- 17-one, melting at about 130432. It displays an optical rotation of +87 in chloroform.-

' 7 Example 2 To a solution of 50 parts of 3abromo-2fl,19- epoxy-5aandrostan-l7-one in 525 parts of acetic acid is added 50 parts of zinc dust, and the resulting reaction mixture is heated at the reflux temperature with stirring for about 7 hours, then is allowed to cool to room temperature. The inorganic salts are removed by filtration and washed on the filter with 'isopropyl alcohol. 'The filtrate is poured slowly into approximately 3000 parts of cold water, and the resulting reaction mixture is stored at -5 for about a 16 hours, The precipitated solid is collected by filtration,

washed on the filter with water, and dried in air to yield crude 19-acetoxy-5Ix-androst-Z-en-1?;one, melting at about 71- 72. Recrystallization of that product from aqueous methanol affords needle-like crystals of the pure substance, melting at about 72-74". This compound is characterized byan optical rotation of 107.5 in chloroform:

1 Example 3 To a solution of 1.5 partsof l9-acetoxy-5a-androst-2- en-17-one in 120 parts of ethanol is added 0.2 part of Those 17a (lower alkyl) 17,8 ols of this invention i wherein the alkyl group has more than one carbon atom can be manufactured also by catalytic hydrogenation of the corresponding 17a-(lower alkynyl)-1'7B-ols. A specific example of the method involved is given by the hydrogenation of 17a-ethynyl-5a-androstane-17,8,19-diol, typically with a 5% palladium-on-carbon catalyst, thus affording 117 a-ethyl-5o=androstane-17,3,lgadiol. V V

In addition to the manufacturing processes described hereinbefore, the compounds of this invention'in which no carbon-to-carbonunsaturated linkages'exist', canalter- V natively be produced by catalytic hydrogenation o'f the corresponding 5a-androst- -ene' compounds: An example of the preferred procedure isg'iven above, i.e.-,- the conversion o f 19 -acetoxy 5ouaridrost-2-en-l7-one. to 1 9-acetoxy-5oc-androstan-l7 -one by hydrogenation with a palladium catalyst.

The compounds of the present invention are useful as a result of their valuable antibiotic properties. They are anti-bacterial, anti-algal, and anti-protozo'al' agents, 'for example, as is evidenced by their'ability to inhibit the growth of Diplococcus p'neumoniae, Chlorellzi Vulgar-is,

and T etrahymena gellel'i.

. T he invention will appear more fully from the examples which follow. These examples'are set fortliby way of illustration only, and it Will be understood that the invention is not to'be construed as limited in spirit or in'scope by the detailsc'ontained therein as many modifications in materials and methods will be apparent; from the disclosure to those skilled in the art. Inthese examples, temperatures are given in" degrees centigrade 0.). Quarttities of materials are expressed in parts by weightunles's otherwise noted. 7

" Example 1 V i To a solution of 18.5 parts" of 3a-hromo-2firhydrox 5uaandnostan-17-one in 1600 parts of carbon tetrachloride is added 67 parts of lead tetraacetate and 25.4 parts of iodine, and the resulting reaction mixture is heated'at the reflux temperature for about 8 hours, then is allowed to stand at room temperature for about 16; hours. The mixture' is filtered, and thefilter cake is washed with methylene chloride. This organic solution is Washed-successively with aqueous sodium thiosulfateand'water,

then is dried over anhydrous sodium sulfate and stripped V of solvent at reduced pressure. The residue is'dissolved onatio CH3 0 H2 ll Plc 4 Eica A mixture of one part of 19 acetoxy-5m-androstan-17-. one, 3 parts of lithium tri-(tertiary-butoxy) aluminum 7 hydride, and 27 parts of tetrahydrofuran is stirred at 05 forabout 1 /2 hours, then is poured into a mixture of ice and Water. 'The precipitate which forms is collected by filtration, washed on the filter with Water, and dried in air to alford the crude product. Crystallization of that solid I from methanol containing decolorizing'carbon afiords pure 5a-androstane-17B';19- diol 19-acetate, melting at about 136-138". It displays an optical rotation of +9 in chloroform and isrepresented by the structural formula 5 Example 5 To a solution of 25 parts by volume of ethereal 3 molar methyl magnesium bromide in 14 parts of ether is added a solution of one part of l9-acetoxy-5a-androstan- 17-one in 49 parts of ether over a period of about 15 minutes. The reaction mixture is heated at the reflux temperature for about 16 hours, then is poured into a mixture of ice and water containing 30 parts of hydrochloric acid. That acidic mixture is extracted with ethyl acetate, and the organic layer is separated, washed with 5% aqueous sodium bicarbonate, and dried over anhydrous potassium carbonate containing decolorizing carbon. Removal of the solvent by distillation at reduced pressure affords a white solid which is recrystallized from acetone-hexane to produce 17oz-methyl-5ot-androstane-17fi,19-diol, melting at about 169-171". An optical rotation of 2 is observed in chloroform. This compound can be represented by the structural formula Example 6 To a slurry of one part of lithium aluminum hydride in 31.5 parts of tetrahydrofuran is added dropwise, at room temperature with stirring, a solution of 1.1 parts of 19acetoxy-5e-androstan-17-oue in 31.5 parts of tetrahydrofuran, and the resulting reaction mixture is heated at the reflux temperature for about 3 hours, then is allowed to stand at room temperature for about 16 hours. The unreacted reagent is decomposed by the successive addition of 30 parts of dioxane containing one part of water, 0.75 part by volume of 20% aqueous sodium hydroxide, and 3.5 parts of water. The insoluble salts which precipitate are removed by filtration and washed on the filter with dioxane. The filtrate is concentrated to dryness at reduced pressure to afford a solid residue which is recrystallized from aqueous methanol, resulting in pure ot-androstane-175,19-diol, melting at about 170- 172. It displays an optical rotation of {+20.5 in chloroform and is further characterized by the structural formula Example 7 To a solution of 3.5 parts of the 30% lithium acetylide- 70% ethylene diamine complex in 31.5 parts of tetrahydrofuran is added at room temperature with stirring, in a nitrogen atmosphere, a solution of 1.1 parts of 19- acetOXy-Sa-andmstan-17-one in 31.5 parts of tetrahydrofuran. Stirring at room temperature is continued for about 2 hours, after which time the mixture is allowed to stand at that temperature for about 16 hours. The reaction mixture is quenched by pouring slowly into approximately 200 parts by volume of aqueous ammonium chloride containing cracked ice, and that aqueous mixture is then made acidic by the addition of dilute hydrochloric acid. The precipitate which forms is iso- Example 8 To a mixture of 7.5 parts of Sa-androstane-l7 8,l9-diol l9-acetate with 100 parts of pyridine is added 50 parts of acetic anhydride, and the resulting mixture is allowed to react at room temperature over a period of about 16 hours. It is then poured into a mixture of ice and water, resulting in formation of an oily precipitate. That material is isolated by filtration, and the filter cake is Washed with water. Purification of that crude product is etlected by recrystallization from aqueous methanol, thus aiiording SO'rEiHdI'OStZlHG-l7a,:i9-di0l 17,19-diacetate which exhibits a melting point at about 77.5-78.5 and is further characaterized by the following structural representation OCOCHa Example 9 To a solution of 1.75 parts of 17a-ethynyl-5ot-andro stane-17fl,19-diol in 200 parts of ethanol is added 0.2 part of 5% palladium-on-carbon catalyst, and that hydrogenation mixture is shaken in a hydrogen atmosphere at room temperature and atmospheric pressure until there is no further uptake of gas. The reaction mixture is then filtered in order to separate the catalyst, and the catalyst is washed on the filter with ethanol. The filtrate is submitted to distillation at reduced pressure, and the solid crude product which remains is recrystallized from aqueous ethanol, thus affording pure 17a-ethyl-5a-androstane-17fl,19-diol. This substance is characterized by a melting point at about 141-143 and displays an optical rotation of +8 in chloroform. It is structurally illustrated by the following formula Tomcat Example 10 7 To a solution of 9 parts of 17qz-ethynyl-5a-androstane- 175,19-diol in 1500 parts of pyridine is added one part of 5% palladium-Von-carbon catalyst, and that mixture is shaken with hydrogen at atmospheric pressure and room temperature until such time as the uptake of one molecular equivalent of hydrogen is completed. The catalyst is separated from the mixture by filtration and is washed well on the filter with ethanol. 1 Concentration of the filtrate to approximately /2 the original volume by distillation at reduced pressure followed by dilution of that solution with water and cooling at -5 results in precipitation of the crude product, which is isolated by filtration and washed Well on the filter with Water. That crude material is purified by recrystallization from aqueous methanol to atford pure 17a-vinyl-5a-androstane-175,19- vdiol hemihydrate, displaying a melting point at about 142-'l45 and characterized also by an optical rotation of +46 in chloroform. This substance can be represented by the structural formula OH CH3 OH t -CHECK,

Ex m ie 11 .A solution of 6 parts of l-butyne in 40 parts of cold ether is added portion'wise, in the course of about 30 minutes, to a solution of butyllithiufn, which is prepared from 17.3 parts of l-bromobutane and 2.2 parts of lithium wire in 27 parts of ether, After completion of the addition, this mixture is stirred for about 90' minutes at about 0. To the resulting ethereal solution of butynyl lithium is then added, over a period of about 30 minutes,

a solution of 11.7 parts of *19-acetoxy-5aandrostan-l7-one in 100 parts of tetrahydrofuran. After completion of the addition, the ether is removed by distillation, keeping the volume essentially constant by the addition of tetrahydrofuran. Thatmixture is then heated at the reflux temperature for about 3 hours, following which period of time it is OH (l; OH v Ecizin'ple 12 The partial reduction of 9.8 parts of 17a-(1 butynyl)- m-andr0stane-17fi,1 9-diol according to the procedure described in, Example 10 results in 17a-(l-butenyl)-5u-an- V V 8 V drostane-l7 6,19-diol, characterized by the following structural representation Example 13 tion, then is washed on the filter with water, and finally is dried in air. That solid material is purified by crystallization from acetone-hexane to afford l9-hydroxy-5a1 androstan-l7-one, characterized by the following structural formula a 1.

Example 14' Q then dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, resulting in 19-propionoxy-h-androstan17-one of the structural formula II 0113011100 CH3 Example 5 By substituting 1.04 parts of l9-propionoxy-5a-androstan-17 one and otherwise proceeding according to the processes described in Example 4, 5u-androstane-17fl,l9- diol '19-propionate, represented by the structural formula ll ornon o 0 8 CH2(\ II is produced.

Example 16 The reaction of 7.8 parts of fia-androstane-im,19-diol with 64.7 parts of propionic anhydride and 100 parts of pyridine by the procedure described in Example 8 results in Sa-androstane-li'fi,19 diol 17,19-dipropionate of the structural formula 0 CH3 CHaCHa 0 ll 0 C-CHgCH;

Example 17 The reaction of 6.9 parts of 17u-methyl-5e-androstane- 175,19-dio1 with acetic anhydride and pyridine by the procedure described in Example 8 results in flat-methyl- Sa-androstane-I7;8,19-diol 19-acetate, represented by the structural formula 0 ona d 0 OH OH, MOE:

Example 18 The substitution of 7.1 parts of l7oc-6thYnYl-5a-8ndl0- stane-l7 8,l9-diol for a-androstane-17B,l9-diol 19-acetate in the processes of Example 8 alfords l7u-ethynyl- Son-androstane-Ufi,19-diol 19-acetate, characterized by the following structural representation ll onto 0 CH3 OH H2 1 9 Example 19 When 7.1 parts of 17a-viny1-5a-androstane178,19-di01 is allowed to react with acetic anhydride and pyridine by the method disclosed in Example 8, 17a-vinyl-5a-androstane-i17B,19-diol l9-acetate is vproduced. It is represented by the following structural formula omdo . OH H:

What is claimed is: 1. A member selected from the class consisting of compounds represented by the formulas wherein X is selected from the group consisting of hydrogen and a lower aliphatic hydrocarbon radical, Y is hydrogen when X is a lower aliphatic hydrocarbon radical, Y is selected from the group consisting of hydrogen and radicals when X is hydrogen, and Z is a member of the class consisting of hydrogen and l i7- (lower alkyl) radicals.

2. 5cz-androstane-17fi,19-diol.

11': 3. A compound of the formula H CH3 H 7 V 0H 7 fiow'ei aliphetic hydrocarbon) O 7 (lower alkyl) 0 7 CH3 9. a-androstane-17p,19-dio1 19-cetate. 10. A compound of the formula r 12 O 1 CH3.

Il- 1 (lower alkyl) C? E! 11. SwandrOStane-IHZ,19-dio1 17,19-diacetate. V 12. A compound of the formula (lower alkyDOO 6 2 011, ll

13. 19-acetoxy-5q-androstan-17-one.

I No references cited.

LEWIS GOTTS, Prim'dfy Examiner.

n OC-(lower alkyl) 

1. A MEMBER SELECTED FROM THE CLASS CONSISTING OF COMPOUNDS REPRESENTED BY THE FORMULAS 